ClinVar Miner

Submissions for variant NM_001127500.3(MET):c.3335A>G (p.His1112Arg) (rs121913243)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000433739 SCV000505127 likely pathogenic Kidney Carcinoma 2015-07-14 no assertion criteria provided literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079490 SCV000111372 pathogenic not provided 2013-10-15 criteria provided, single submitter clinical testing
GeneDx RCV000079490 SCV000617599 pathogenic not provided 2017-10-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted MET c.3335A>G at the cDNA level, p.His1112Arg (H1112R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant has been shown to segregate with disease in two large kindreds with hereditary papillary renal carcinoma and has been reported in other individuals with familial or bilateral papillary renal cell carcinoma (Fischer 1998, Schmidt 1998, Chartier 2017). In vivo functional assays found this variant to result in malignant transformation of transfected cells and cause tumor development in a mouse model (Schmidt 1998). MET His1112Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. MET His1112Arg occurs at a position that is conserved across species and is located in the protein kinase domain (UniProt). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000014901 SCV000553291 pathogenic Renal cell carcinoma, papillary, 1 2017-02-16 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1112 of the MET protein (p.His1112Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs121913243, ExAC 0.004%). This variant has been reported to segregate with hereditary papillary renal cell carcinoma in 2 families with a likely common ancestral founder (PMID: 9563489). This variant has also been reported in individuals affected with sporadic papillary renal cell carcinoma (PMID: 9563489, 10327054, 23213094). This variant is also known as H1094R in the literature. ClinVar contains an entry for this variant (Variation ID: 13887). From an analysis of 22 affected carriers in 2 large families, the estimated risk of developing papillary renal carcinoma by age 40 years was 19% (95% CI, 5-34%). This risk increased to 67% (95% CI, 46-87%) by 60 years of age, suggesting that this variant confers later-onset malignancy with intermediate penetrance (PMID: 9563489). Experimental studies have shown that this missense change induces malignant cellular transformation (PMID: 9563489). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014901 SCV000035156 pathogenic Renal cell carcinoma, papillary, 1 1998-09-01 no assertion criteria provided literature only

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